Heart failure is a major medical problem of the modern society and 1 in 9 deaths in the United States (2007) is caused by heart failure. The heart is a high energy-demanding organ that uses fatty acids as the major fuel source. However, under stressed conditions such as cardiomyopathy, the stressed myocardium often switches energy usage preference from lipid to glucose. Intriguingly, elevated expression of COUP-TFII was observed in stressed hearts of non-ischemic cardiomyopathy patients and also in a pressure overload mouse model. To investigate the role of COUP-TFII in cardiac dysfunction, we generated a mouse model over-expressing COUP- TFII specifically in the cardiomyocytes. Our preliminary results showed that over-expression of COUP-TFII results in the suppression of the expression of key enzymes essential for fatty acid trafficking and oxidation, suggesting a switch of fuel usage. The expression of many enzymes involved in fatty acid metabolism is regulated by the PGC/ERR axis. Interestingly, we also showed reduced expression of PGC1/ and ERR/, thus strongly implicating COUP-TFII as a regulator for controlling the PGC/ERR axis to alter fuel usage and mitochondrial function, leading to dysregulation of energy metabolism. Interestingly, we also showed that mice over-expressing SRC-2 also reduces lipid usage in the cardiac muscle, phenotypes analogous to COUP-TFII over-expression. Taken together, we hypothesize that COUP-TFII and SRC-2 act jointly to control cardiac function through modulating the expression of key genes involved in energy metabolism. To dissect the role of COUP-TFII and SRC-2 in the dysregulation of cardiac energy metabolism, three specific aims are proposed: 1. Dissect the role of COUP-TFII in the regulation of cardiac energy metabolism; 2. Identify pathways regulated by COUP-TFII in the heart and 3. Investigate the functional interaction between COUP-TFII and SRC- 2 in regulating cardiac fuel usage. These studies will increase our understanding of how COUP-TFII and SRC-2 jointly regulate transcriptional networks in cell types that are pivotal in the regulation of metabolic pathways that govern energy homeostasis in vivo.